Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal hyperinflammatory syndrome characterized by the uncontrolled immune activation of cytotoxic T lymphocytes, natural killer cells, and macrophages, resulting in cytokine storm-mediated multiorgan injury [1]. Based on the underlying etiology, HLH is generally classified as primary or secondary. Primary HLH (pHLH) mainly presents in childhood and is associated with mutations in genes such as PFR1, STX11, UNC13D, and STXBP2. Secondary HLH (sHLH) is usually caused by infection, autoimmune disease, and malignancies [[2], [3], [4]]. Among them, lymphoma-associated HLH (LAHS) is the major type of HLH caused by malignancies and exhibits an extremely poor outcome [5]. Generally, the unfavorable prognosis is partly attributed to a lack of early identification of HLH and its underlying disease. In actual clinical work, the symptoms of sHLH can be non-specific, often overlapping with those of underlying lymphoma itself or concurrent infections, which leads to misdiagnosis or delayed diagnosis. On the other hand, for patients with HLH as the initial manifestation, identifying the underlying etiology of HLH represents another challenge.

Regarding the subtypes of underlying lymphoma in LAHS, multiple studies have shown that T/NK cell lymphoma is the most common type triggering sHLH [6]. However, increasing evidence suggests that the proportions of B cell lymphoma-associated HLH (B-LAHS) and T/NK cell lymphoma-associated HLH (T/NK-LAHS) were comparable. A recent large systematic analysis revealed that 45.2 % of patients with LAHS were associated with T-cell lymphoma, and 45.6 % with B-cell lymphoma. DLBCL was the main underlying lymphoma subtype in B-LAHS cases [[7], [8]]. Thus, DLBCL-associated HLH (DLBCL-HLH) is worth focusing on. Intriguingly, a previous study reported that B-LAHS patients exhibited a relatively lower ferritin level and a higher sCD25/ferritin ratio compared to T-LAHS patients, which indicates that B-LAHS has unique clinical and laboratory parameters [8]. Identifying the clinical and laboratory features of DLBCL-HLH may contribute to the early detection and intervention of the disease.

Recently, as an essential link in the pathogenesis of HLH, cytokine storms have received much attention. For instance, the level of serum soluble CD25 (sCD25) /IL-2 receptor α (IL-2Ra) is listed as one of the clinical diagnostic criteria for HLH [4]. Other cytokines, such as interferon-gamma (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-10, IL-12, and IL-18, which are not yet diagnostic criteria for HLH, are valued in diagnosis, potential disease classification, and prognosis prediction [[9], [10], [11]]. Of note, HLH triggered by different underlying etiologies exhibits distinct cytokine profiles. For instance, IFN-γ and IL-10 were markedly elevated in EBV-associated HLH. Serum IL-6 and IL-18 levels substantially increased in autoimmune disorders associated HLH [12,13]. Several studies have also reported the cytokine profiles in LAHS and used them as early predictors for LAHS diagnosis [14,15]. However, these studies did not specifically classify the subtypes of lymphoma, and primarily included NK/T-cell lymphoma. The available data regarding serum cytokine levels in DLBCL associated HLH remain very limited.

As with the difficulties and importance of early identification of sHLH in patients with DLBCL, we aimed to find reliable biomarkers for the early identification of DLBCL-HLH. Thus, this retrospective study was designed to compare the clinical and laboratory parameters, especially the serum cytokine patterns in DLBCL patients with or without HLH, so as to determine differential markers to support the diagnosis of DLBCL-HLH.